TY - JOUR
T1 - A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors
AU - Britten, Carolyn D.
AU - Garrett-Mayer, Elizabeth
AU - Chin, Steven H.
AU - Shirai, Keisuke
AU - Ogretmen, Besim
AU - Bentz, Tricia A.
AU - Brisendine, Alan
AU - Anderton, Kate
AU - Cusack, Susan L.
AU - Maines, Lynn W.
AU - Zhuang, Yan
AU - Smith, Charles D.
AU - Thomas, Melanie B.
N1 - Funding Information:
This work was supported in part by the FDA (1R01FD004102), the Pennsylvania Department of Health (SAP#4100061668), the Lipidomics, Biostatis-tics, and Clinical Trials Office Shared Resources at Hollings Cancer Center, Medical University of South Carolina (P30 CA138313), and the South Carolina Clinical and Translational Research Institute, Medical University of South Carolina (NIH/NCATSUL1TR000062). M.B. Thomas, C.D. Britten, and C.D. Smith also received support from the South Carolina Centers of Economic Excellence. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding Information:
This work was supported in part by the FDA (1R01FD004102), the Pennsylvania Department of Health (SAP#4100061668), the Lipidomics, Biostatistics, and Clinical Trials Office Shared Resources at Hollings Cancer Center, Medical University of South Carolina (P30 CA138313), and the South Carolina Clinical and Translational Research Institute, Medical University of South Carolina (NIH/NCATSUL1TR000062). M.B. Thomas, C.D. Britten, and C.D. Smith also received support from the South Carolina Centers of Economic Excellence.
Publisher Copyright:
©2017 AACR.
PY - 2017/8/15
Y1 - 2017/8/15
N2 - Purpose: Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABC294640, a first-in-class orally available inhibitor of SK2. Experimental Design: Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid, and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results: Twenty-two patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting, and fatigue. Among the 4 patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and 2 were unable to complete cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the recommended phase II dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions: At 500 mg bid, ABC294640 is well tolerated and achieves biologically relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.
AB - Purpose: Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABC294640, a first-in-class orally available inhibitor of SK2. Experimental Design: Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid, and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results: Twenty-two patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting, and fatigue. Among the 4 patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and 2 were unable to complete cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the recommended phase II dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions: At 500 mg bid, ABC294640 is well tolerated and achieves biologically relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.
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U2 - 10.1158/1078-0432.CCR-16-2363
DO - 10.1158/1078-0432.CCR-16-2363
M3 - Article
C2 - 28420720
AN - SCOPUS:85028073704
SN - 1078-0432
VL - 23
SP - 4642
EP - 4650
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -